Herbert W Virgin

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (200)1859.53 Total impact

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    ABSTRACT: The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1(-/-) mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair. Downstream of type I IFN signaling, the highly related IFN-stimulated genes Apolipoprotein L9a and b activate epithelial proliferation through ERK activation. Our findings demonstrate that the host immune response to chronic viral infection has systemic effects on epithelial turnover through a myeloid-epithelial circuit. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe. 12/2014;
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    ABSTRACT: Norovirus gastroenteritis is a major public health burden worldwide. Although fecal shedding is important for transmission of enteric viruses, little is known about the immune factors that restrict persistent enteric infection. We report here that while the cytokines interferon α (IFNα) and IFNβ prevented the systemic spread of murine norovirus (MNoV), only IFNλ controlled persistent enteric infection. Infection-dependent induction of IFNλ was governed by the MNoV capsid protein and correlated with diminished enteric persistence. Treatment of established infection with IFNλ cured mice in a manner requiring non-hematopoietic cell expression of the IFNλ receptor, Ifnlr1, and independent of adaptive immunity. These results suggest the therapeutic potential of IFNλ for curing virus infections in the gastrointestinal tract. Copyright © 2014, American Association for the Advancement of Science.
    Science (New York, N.Y.). 11/2014;
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    ABSTRACT: The capacity of human norovirus (NoV), which causes >90% of global epidemic nonbacterial gastroenteritis, to infect a subset of people persistently may contribute to its spread. How such enteric viruses establish persistent infections is not well understood. Here, we report that antibiotics prevented persistent murine norovirus (MNoV) infection, an effect that was reversed by replenishment of the bacterial microbiota. Antibiotics did not prevent tissue infection or affect systemic viral replication, but acted specifically in the intestine. The receptor for the antiviral cytokine interferon-λ (IFNλ), Ifnlr1, as well as the transcription factors Stat1 and Irf3 were required for antibiotics to prevent viral persistence. Thus, the bacterial microbiome fosters enteric viral persistence in a manner counteracted by specific components of the innate immune system. Copyright © 2014, American Association for the Advancement of Science.
    Science (New York, N.Y.). 11/2014;
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    ABSTRACT: Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses are overlapping, and both exhibit pre-existing humoral and cellular immunity in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. These novel rhesus adenovirus vectors exhibited extremely low seroprevalence in sub-Saharan human populations and proved comparably immunogenic to human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. Although there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this manuscript, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Journal of virology. 11/2014;
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    ABSTRACT: The importance of autophagy in the generation of memory CD8(+) T cells in vivo is not well defined. We report here that autophagy was dynamically regulated in virus-specific CD8(+) T cells during acute infection of mice with lymphocytic choriomeningitis virus. In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8(+) T cells and was then upregulated when the cells stopped dividing just before the contraction phase. Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells. Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy.
    Nature immunology. 11/2014;
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    Dataset: mmc3
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    Dataset: mmc1
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    Dataset: mmc4
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    Dataset: mmc2
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    ABSTRACT: Mammals are co-infected by multiple pathogens that interact through unknown mechanisms. We found that helminth infection, characterized by the induction of the cytokine interleukin-4 (IL-4) and the activation of the transcription factor Stat6, reactivated murine gammaherpesvirus infection in vivo. IL-4 promoted viral replication and blocked the antiviral effects of interferon-γ (IFNγ) by inducing Stat6 binding to the promoter for an important viral transcriptional transactivator. IL-4 also reactivated human Kaposi's sarcoma associated herpesvirus from latency in cultured cells. Exogenous IL-4 plus blockade of IFNγ reactivated latent murine gammaherpesvirus infection in vivo, suggesting a "two-signal" model for viral reactivation. Thus chronic herpesvirus infection, a component of the mammalian virome, is regulated by the counterpoised actions of multiple cytokines on viral promoters that have evolved to sense host immune status.
    Science (New York, N.Y.). 06/2014;
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    ABSTRACT: Autophagy is a lysosomal degradation pathway that is important in cellular homeostasis. Prior work showed a key role for the autophagy related 5 (Atg5) in resistance to Toxoplasma gondii. Here we show that the cassette of autophagy proteins involved in the conjugation of microtubule-associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine, including Atg7, Atg3, and the Atg12-Atg5-Atg16L1 complex play crucial roles in the control of T. gondii in vitro and in vivo. In contrast, pharmacologic modulation of the degradative autophagy pathway or genetic deletion of other essential autophagy genes had no substantial effects. Rather the conjugation system was required for targeting of LC3 and interferon-γ effectors onto the vacuolar membrane of T. gondii and its consequent disruption. These data suggest that the ubiquitin-like conjugation systems that reorganize intracellular membranes during canonical autophagy are necessary for proper targeting of immune effectors to the intracellular vacuole membranes utilized by pathogens.
    Immunity 06/2014; · 19.80 Impact Factor
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    ABSTRACT: Human noroviruses are a major cause of epidemic and sporadic gastroenteritis worldwide and can chronically infect immunocompromised patients. Efforts to develop effective vaccines and antivirals have been hindered by the uncultivable nature and extreme genetic diversity of human noroviruses. Although they remain a particularly challenging pathogen to study, recent advances in norovirus animal models and in vitro cultivation systems have led to an increased understanding of norovirus molecular biology and replication, pathogenesis, cell tropism, and innate and adaptive immunity. Furthermore, clinical trials of vaccines consisting of nonreplicating virus-like particles have shown promise. In this review, we summarize these recent advances and discuss controversies in the field, which is rapidly progressing toward generation of antiviral agents and increasingly effective vaccines.
    Cell host & microbe. 06/2014; 15(6):668-680.
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    ABSTRACT: A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3- and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell type- and pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.
    Proceedings of the National Academy of Sciences 05/2014; · 9.81 Impact Factor
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    Jason M. Norman, Scott A. Handley, Herbert W. Virgin
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    ABSTRACT: Advanced sequencing techniques have shown that bacteria are not the only complex and important microbes in the human intestine. Non-bacterial organisms, particularly the virome and the mycobiome, are important regulators of intestinal immunity and inflammation. The virome is mucosal and systemic; it can alter the host response to bacteria and interact with host genes and bacteria to contribute to disease pathogenesis. The human mycobiome is also complex and can contribute to intestinal inflammation. We review what has recently been learned about the non-bacterial and non-archaeal microbes in the gastrointestinal tract, discussing their potential effects on health and disease and analytical approaches for their study. Studies of associations between the microbiome and intestinal pathology should incorporate kingdom-agnostic approaches if we are to fully understand intestinal health and disease.
    Gastroenterology 05/2014; · 12.82 Impact Factor
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    ABSTRACT: A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3- and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell type- and pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.
    Proceedings of the National Academy of Sciences 05/2014; · 9.81 Impact Factor
  • Herbert W Virgin
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    ABSTRACT: The virome contains the most abundant and fastest mutating genetic elements on Earth. The mammalian virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. Virome interactions with the host cannot be encompassed by a monotheistic view of viruses as pathogens. Instead, the genetic and transcriptional identity of mammals is defined in part by our coevolved virome, a concept with profound implications for understanding health and disease.
    Cell 03/2014; 157(1):142-150. · 31.96 Impact Factor
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    ABSTRACT: The essential immediate-early transcriptional activator RTA, encoded by gene 50, is conserved among all characterized gammaherpesviruses. Analyses of a recombinant murine gamma-herpesvirus 68 lacking both of the known gene 50 promoters (G50pDblKO) revealed that this mutant retained the ability to replicate in the simian kidney epithelial cell line Vero, but not in permissive murine fibroblasts following low MOI infection. However, G50pDblKo replication in permissive fibroblasts was partially rescued by high MOI infection. In addition, replication of the G50pDblKO virus was rescued by growth on MEFs isolated from IFNα/βR(-/-) mice, while growth on Vero cells was suppressed by the addition of IFNα. 5' rapid amplification of cDNA ends (RACE) analyses of RNA prepared from G50pDblKo and wild-type MHV68 infected murine macrophages identified three novel gene 50 transcripts initiating from 2 transcription initiation sites located upstream of the currently defined proximal and distal gene 50 promoters. In transient promoter assays neither of the newly identified gene 50 promoters exhibited sensitivity to IFNα treatment, although RTA levels were lower in IFNα-responsive cells infected with the G50pDblKo mutant. Infection of mice with the MHV68 G50pDblKo virus demonstrated that this mutant virus was able to establish latency in the spleen and peritoneal exudates cells (PECs) of C57Bl/6 mice with about 1/10 the efficiency of wild-type virus or marker rescue virus. However, despite the ability to establish latency, the G50pDblKo virus mutant was severely impaired in its ability to reactivate from either latently infected splenocytes or PECs. Consistent with the ability to rescue replication of the G50pDblKO mutant by growth on type I interferon receptor null MEFs, infection of IFNα/βR(-/-) mice with the G50pDblKo mutant virus demonstrated partial rescue of: (i) acute virus replication in the lungs; (ii) establishment of latency; and (iii) reactivation from latency. The identification of additional gene 50/RTA transcripts highlight the complex mechanisms involved in controlling expression of RTA, likely reflecting time dependent and/or cell-specific roles of different gene 50 promoters in controlling virus replication. Furthermore, the newly identified gene 50 transcripts may also act as negative regulators that modulate RTA expression. The viral transcription factor RTA, encoded by open reading frame 50 (Orf50), is well conserved among all known gammaherpesviruses and is essential for both virus replication and reactivation from latently infected cells. Previous studies have shown that regulation of gene 50 transcription is complex. The studies reported here describe the presence of additional alternatively initiated, spliced transcripts that encode RTA. Understanding how expression of this essential viral gene product is regulated may identify new strategies for interfering with infection in the setting of gammaherpesvirus-induced diseases.
    Journal of Virology 02/2014; · 5.08 Impact Factor
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    ABSTRACT: The mammalian intestine is colonized by beneficial commensal bacteria and is a site of infection by pathogens, including helminth parasites. Helminths induce potent immunomodulatory effects, but whether these effects are mediated by direct regulation of host immunity or indirectly through eliciting changes in the microbiota is unknown. We tested this in the context of virus-helminth coinfection. Helminth coinfection resulted in impaired antiviral immunity and was associated with changes in the microbiota and STAT6-dependent helminth-induced alternative activation of macrophages. Notably, helminth-induced impairment of antiviral immunity was evident in germ-free mice, but neutralization of Ym1, a chitinase-like molecule that is associated with alternatively activated macrophages, could partially restore antiviral immunity. These data indicate that helminth-induced immunomodulation occurs independently of changes in the microbiota but is dependent on Ym1.
    Science. 01/2014; 345(6196):578-82.
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    ABSTRACT: ABSTRACT Pervasive transcription is observed in a wide range of organisms, including humans, mice, and viruses, but the functional significance of the resulting transcripts remains uncertain. Current genetic approaches are often limited by their emphasis on protein-coding open reading frames (ORFs). We previously identified extensive pervasive transcription from the murine gammaherpesvirus 68 (MHV68) genome outside known ORFs and antisense to known genes (termed expressed genomic regions [EGRs]). Similar antisense transcripts have been identified in many other herpesviruses, including Kaposi's sarcoma-associated herpesvirus and human and murine cytomegalovirus. Despite their prevalence, whether these RNAs have any functional importance in the viral life cycle is unknown, and one interpretation is that these are merely "noise" generated by functionally unimportant transcriptional events. To determine whether pervasive transcription of a herpesvirus genome generates RNA molecules that are functionally important, we used a strand-specific functional approach to target transcripts from thirteen EGRs in MHV68. We found that targeting transcripts from six EGRs reduced viral protein expression, proving that pervasive transcription can generate functionally important RNAs. We characterized transcripts emanating from EGRs 26 and 27 in detail using several methods, including RNA sequencing, and identified several novel polyadenylated transcripts that were enriched in the nuclei of infected cells. These data provide the first evidence of the functional importance of regions of pervasive transcription emanating from MHV68 EGRs. Therefore, studies utilizing mutation of a herpesvirus genome must account for possible effects on RNAs generated by pervasive transcription. IMPORTANCE The fact that pervasive transcription produces functionally important RNAs has profound implications for design and interpretation of genetic studies in herpesviruses, since such studies often involve mutating both strands of the genome. This is a common potential problem; for example, a conservative estimate is that there are an additional 73,000 nucleotides transcribed antisense to annotated ORFs from the 119,450-bp MHV68 genome. Recognizing the importance of considering the function of each strand of the viral genome independently, we used strand-specific approaches to identify six regions of the genome encoding transcripts that promoted viral protein expression. For two of these regions, we mapped novel transcripts and determined that targeting transcripts from these regions reduced viral replication and the expression of other viral genes. This is the first description of a function for these RNAs and suggests that novel transcripts emanating from regions of pervasive transcription are critical for the viral life cycle.
    mBio 01/2014; 5(2). · 6.88 Impact Factor
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    ABSTRACT: The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in over 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D induced early expression of GCN2 in the blood strongly correlates with the magnitude of the later CD8(+) T cell response. Here we demonstrate a key role for virus induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4(+) and CD8(+) T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.
    Science 12/2013; · 31.20 Impact Factor

Publication Stats

11k Citations
1,859.53 Total Impact Points

Institutions

  • 1995–2014
    • Washington University in St. Louis
      • • Department of Pathology and Immunology
      • • Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (MRCE)
      San Luis, Missouri, United States
  • 2012–2013
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
    • Donald Danforth Plant Science Center
      San Luis, Missouri, United States
  • 2007–2013
    • University of Texas Southwestern Medical Center
      • Department of Microbiology
      Dallas, Texas, United States
    • San Diego State University
      • Department of Biology
      San Diego, California, United States
  • 1985–2013
    • Harvard Medical School
      • • Department of Pathology
      • • Department of Microbiology and Immunobiology
      Boston, Massachusetts, United States
  • 1993–2012
    • University of Washington Seattle
      • • Department of Immunology
      • • Department of Pathology
      • • Department of Medicine
      Seattle, WA, United States
  • 2009–2011
    • University of Texas Medical Branch at Galveston
      • Department of Pathology
      Galveston, Texas, United States
    • Centers for Disease Control and Prevention
      • Division of Viral Diseases
      Atlanta, MI, United States
  • 2008
    • Mount Sinai School of Medicine
      • Department of Microbiology
      Manhattan, NY, United States
    • University of North Carolina at Chapel Hill
      • Department of Microbiology and Immunology
      North Carolina, United States
    • The Scripps Research Institute
      La Jolla, California, United States
  • 2006
    • State University of New York Upstate Medical University
      • Department of Microbiology and Immunology
      Syracuse, New York, United States
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
    • New York University
      • Department of Medicine
      New York City, NY, United States
  • 2002–2003
    • Emory University
      • Department of Microbiology and Immunology
      Atlanta, GA, United States
  • 1993–2003
    • University of Colorado
      • • Department of Microbiology
      • • Department of Neurology
      Denver, CO, United States
  • 1998
    • Eastern Virginia Medical School
      • Department of Microbiology and Molecular Cell Biology
      Norfolk, Virginia, United States
  • 1996
    • University of Western Australia
      Perth City, Western Australia, Australia